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Age-related dopaminergic innervation augments Th2 inflammation in the postnatal lung

ABSTRACT: The goal of this assay is to investigate the signaling pathways involved in dopamine's promotion on Th2 differentiation and proliferation and to clarify the role of dopaminergic nerve innervation in neonatal asthma pathogenesis, to help identifying potential targets for therapy. To do that, we isolated naïve CD4+ T cells from spleens of non-transgenic C57BL/6 mice according to established protocols, and we cultured them under Th0 condition with/without dopamine treatment. To obtain an unbiased view of gene regulation in mouse CD4+ T cells exposed to dopamine, we analyzed the transcriptome of untreated control CD4+ T cells ('Th0') and dopamine-treated CD4+ T cells ('Th0+Dopa') via explorative RNA-sequencing.

ORGANISM(S): Mus musculus

PROVIDER: GSE137968 | GEO | 2019/09/26

REPOSITORIES: GEO

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Project description:L-3,4-dihydroxyphenylalanine (levodopa) treatment is the major pharmacotherapy for Parkinson's disease. However, almost all patients receiving levodopa eventually develop debilitating involuntary movements (dyskinesia). While it is known that striatal spiny projection neurons (SPNs) are involved in the genesis of this movement disorder, the molecular basis of dyskinesia is not understood. In this study, we identify distinct cell-type-specific gene expression changes that occur in sub-classes of SPNs upon induction of a parkinsonian lesion followed by chronic levodopa treatment. We identify several hundred genes whose expression is correlated with levodopa dose, many of which are under the control of AP-1 and ERK signaling. In spite of homeostatic adaptations involving several signaling modulators, AP-1-dependent gene expression remains highly dysregulated in direct pathway SPNs (dSPNs) upon chronic levodopa treatment. We also discuss which molecular pathways are most likely to dampen abnormal dopaminoceptive signaling in spiny projection neurons, hence providing potential targets for antidyskinetic treatments in Parkinson's disease. To profile the cell-type-specific responses of striatal spiny projection neurons (SPNs) to striatal dopamine depletion, we conducted TRAP analysis of the two major classes of these neurons: dSPNs that express the dopamine receptor 1a (Drd1a), and iSPNs that express the dopamine receptor 2 (Drd2). To disrupt dopamine innervation to both of these SPN populations that reside in the striatum, we injected the neurotoxin 6-hydroxydopamine (6-OHDA), unilaterally, in the medial forebrain bundle (MFB) in hemizygous Drd1-TRAP and Drd2-TRAP adult (9-14 weeks) male mice (kept on a C57BL/6J genetic background). This lesion procedure causes nigral dopamine cell death within a few days, along with a widespread and near-complete loss of dopaminergic innervation to the entire dorsal striatum on one side of the brain (a hemiparkinsonian model). We first examined the effects of dopamine depletion alone, compared to a mock lesion (ascorbate / saline injected). We then examined the effects of chronic levodopa treatment upon the molecular profiles of dopamine- depleted dSPNs and iSPNs, with two dose regimens. The ‘high-dose’ L-DOPA regimen (3 mg/kg on days 1-3, followed by 6 mg/kg on days 4-9) was expected to induce severe dyskinesia in all MFB-lesioned mice. The low-dose L-DOPA regimen (1 mg/kg on days 1-3, followed by 2 mg/kg on days 4-9) was expected to reverse limb use asymmetry without causing conspicuous dyskinesias. To equalize the effects of stress and handling across all groups, including control groups, all mice were equally handled and thus received saline injections when not receiving levodopa injections. Each treatment group contained 7-10 replicates. TRAP-purified mRNAs from either Drd1a- or Drd2-expressing SPNs were reverse-transcribed, amplified, and used to interrogate Affymetrix 430_2.0 GeneChip microarrays.

Project description:Symptoms of the dopamine dysregulation syndrome in patients with Parkinsonâs disease (PD) are close to those observed in psychostimulant addiction. This suggests that dopamine replacement therapy shares some properties with potentially addictive drugs. A remaining challenge is to understand the neuroadaptations leading to compulsive dopaminergic medication use. To this end, the reinforcing properties of the D2/D3 agonist pramipexole (PPX) were assessed after chronic exposure to L-dopa in an alpha-synuclein PD rat model. Individual male rats underwent a bilateral nigral loss induced by AAV-mediated alpha-synuclein overexpression. Control sham animals received stereotaxic injection of the same AAV vector enabeling expresion of the GFP. Five weeks after lesion induction, animals received a subcutaneous daily administration of L-dopa methyl-ester (50mg/kg) plus benserazide (12,5mg/kg) or a saline solution. Following this 3 weeks period of chronic treatment, the reinforcing properties of the D2/D3 agonist pramipexole were assessed using a place conditioning paradigm. This procedure consists in pairing a drug with a specific environment and vehicle with another environment during a conditioning period. The first day, animals received an intraperitoneal injection of saline solution before a 20min habituation period that allowed exploration of the apparatus (pre-test). Time spent in each chamber was analyzed. The compartment less occupied by the animal was determined as the drug paired side. The following days, animals received either pramipexole 2mg/kg on days 1, 3, 5 and 7 or vehicle on days 2, 4, 6 and 8 and were placed in the paired-chamber for 40 minutes. Controls groups received saline solution during all conditioning sessions. The day following the last conditioning session, a probe test (post test) was performed with 20min free access to the apparatus after an ip injection of saline solution. Place preference scores were calculated as the difference in time spent in the drug-paired chamber between post-test and pre-test.

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Age-related dopaminergic innervation augments Th2 inflammation in the postnatal lung

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